We first established that we were able to restrict our manipulation to the CA1 region of the hippocampus to target specific neural populations. Next we confirmed that eIF2 phosphorylation and subsequent ATF4 translation is induced upon drug administration predominantly in hippocampal CA1 pyramidal cells, a major output cell of hippocampal memory to cortical/subcortical areas. Consequently, we observed a decrease in CRE (cAMP-responsive element)-dependent gene transcription. . Remarkably, the transgenic mice exhibited a deficit in synaptic plasticity and hippocampal-dependent memory consolidation following drug administration. This result suggests that gene-specific translation, including ATF4 and its downstream molecular pathway, in CA1 pyramidal cells is critical for long-term memory formation and plasticity. Importantly, although we observed significant behavioral deficits, overall levels of protein synthesis in CA1 were not changed after PKR activation. Conversely, when animals were treated with low doses of anisomycin, the most widely used protein synthesis inhibitor, the general inhibition of protein synthesis was not sufficient to induce memory impairments. This double dissociation suggests that general protein synthesis inhibition per se does not contribute to impairments in memory consolidation, and calls into question the amnesia-inducing effect of anisomycin as a protein synthesis inhibitor. By using a genetic manipulation that is both spatially and temporally restricted and acts on a specific intracellular pathway, we are able to investigate the mechanisms underlying the phenomenon of memory consolidation at the cellular level and provide new insight into how the hippocampus contributes to long-term memory formation.